NM_000335.5(SCN5A):c.44G>C (p.Arg15Thr) AND Dilated cardiomyopathy 1E

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 9, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003335133.1

Allele description [Variation Report for NM_000335.5(SCN5A):c.44G>C (p.Arg15Thr)]

NM_000335.5(SCN5A):c.44G>C (p.Arg15Thr)

Gene:

SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.44G>C (p.Arg15Thr)

HGVS:

NC_000003.12:g.38633264C>G
NG_008934.1:g.21409G>C
NM_000335.5:c.44G>CMANE SELECT
NM_001099404.2:c.44G>C
NM_001099405.2:c.44G>C
NM_001160160.2:c.44G>C
NM_001160161.2:c.44G>C
NM_001354701.2:c.44G>C
NM_198056.3:c.44G>C
NP_000326.2:p.Arg15Thr
NP_001092874.1:p.Arg15Thr
NP_001092875.1:p.Arg15Thr
NP_001153632.1:p.Arg15Thr
NP_001153633.1:p.Arg15Thr
NP_001341630.1:p.Arg15Thr
NP_932173.1:p.Arg15Thr
NP_932173.1:p.Arg15Thr
LRG_289t1:c.44G>C
LRG_289:g.21409G>C
LRG_289p1:p.Arg15Thr
NC_000003.11:g.38674755C>G
NM_198056.2:c.44G>C

Protein change:

R15T

Links:

dbSNP: rs373410109

NCBI 1000 Genomes Browser:

rs373410109

Molecular consequence:

NM_000335.5:c.44G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.44G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.44G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.44G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.44G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.44G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.44G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Dilated cardiomyopathy 1E (CMD1E)
Synonyms:: CARDIOMYOPATHY, DILATED, WITH CONDUCTION DEFECT 2; CARDIOMYOPATHY, DILATED, WITH CONDUCTION DISORDER AND ARRHYTHMIA; SCN5A-Associated Dilated Cardiomyopathy
Identifiers:: MONDO: MONDO:0011003; MedGen: C1832680; Orphanet: 154; OMIM: 601154

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004046516	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Mar 9, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004046516

New York Genome Center

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Uncertain significance
(Mar 9, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Details of each submission

From New York Genome Center, SCV004046516.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The c.44G>C variant identified in SCN5A has previously been reported in an individual with Long QT Syndrome, but its pathogenicity remains uncertain [PMID: 31737537]. The variant has been deposited in ClinVar as a Variant of Uncertain Significance by multiple submitters [ClinVar ID: 165163]. The c.44G>C variant is observed in 21 alleles (~0.0036% minor allele frequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, which may include individuals with cardiac disorders. The c.44G>C variant is located in exon 2 of this 28-exon gene and predicted to replace an evolutionarily conserved (in mammals) arginine amino acid with threonine at position 15(p.(Arg15Thr). In silico predictions are inconclusive of damaging effect of the p.(Arg15Thr) variant [CADD v1.6 = 21.1, REVEL = 0.611]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.44G>C p.(Arg15Thr) variant identified in SCN5A is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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